The development and proper function of the nervous system is critically dependent on the actions of neurotrophic factors. There are now two major families of these factors, the neurotrophins and the GDNF Family of Ligands (GFLs). At present, there are four GFLs, GDNF, Neurturin, Persephin and Artemin. These factors signal through a receptor complex composed of the Ret tyrosine kinase and a binding component (a member of a family of GPI-linked coreceptors (GFRalpha family). Experiments using in vitro cultures as well as analysis of gene-targeted mice have shown that GFLs support the survival of dopaminergic midbrain and spinal cord motor neurons as well as peripheral sensory, sympathetic, parasympathetic and enteric neurons. In this proposal, we outline experiments to study the role of Ret signaling in vivo during development as well as in adulthood. The role of GFRalpha expression in cells that lack Ret will be studied in vivo and in vitro, with particular emphasis on its role in influencing nerve regeneration and target innervation. The role of Neurturin in parasympathetic and enteric neuron differentiation and maintenance will be investigated. The physiologic roles of Artemin and Persephin will be investigated by characterizing the phenotypes of mice that lack these factors. Through this type of analysis, neuronal populations (as well as non-neuronal cells) dependent on these factors for survival as well as maintenance and proper function will be identified. Patterns of gene expression induced by Ret signaling will be assayed using microarray methodology. The focus of these studies is to understand the role of the GFLs in influencing the function of the nervous system and to determine whether abnormalities in GFL actions lead to impaired neuronal function or response to injury. This information is vital because these neurotrophic factors may be useful in reversing the neuronal deficits found in neurodegenerative diseases, peripheral neuropathies of chronic diseases such as diabetes, and gut motility syndromes.